Sirer is best known for his contributions to operating systems, distributed systems, and fundamental cryptocurrency research. He developed the SPIN (operating system),[4] where the implementation and interface of an operating system could be modified safely at run-time by type-safe extension code.[5] He also led the Nexus OS effort, where he developed new techniques for attesting to, and reasoning about, the semantic properties of remote programs.[6] His Karma system, published in 2003, is the first cryptocurrency that uses a distributed mint based on proof-of-work.[7][8]

In conjunction with his research group, he published the paper "Majority is not Enough, Bitcoin Mining is Vulnerable" which described the selfish mining attack, an attack on Bitcoin with only 1/3 of total hash power.[9] He also developed Bitcoin-NG, a bitcoin scaling solution,[10] and Bitcoin Covenants, a security solution.[11] He is also co-founder of bloXroute, a company focusing on solving the forgotten "layer 0" networking layer.[12] He is also founder of Ava Labs, a project building the cryptocurrency AVA, and computing platform using Avalanche Consensus.[13]